This program project is concerned with the study of the biology and regulation of the hypothalamo-pituitary-adrenal (HPA) axis, with particular emphasis on peptide biology. The peptides of interest are the hypothalamic neuropeptides, arginine vasopressin (AVP), pro-dynorphin and corticotropin releasing factor (CRF), and the anteror pituitary peptide family, pro- opiomelanocortin (POMC). The four projects involved in this program range from basic animal studies of the dynorphin- vasopressin systems, to clinical human studies of the HPA dysregulation in major depression. Nevertheless, these projects are closely interrelated in terms of attempting to derive a basic understanding of the regulation and dynamics of the HPA axis. This is predicated on the notion that such as improved knowledge base will be useful in elucidating the function of the peptides in this stress-related system, and the responsiveness of the various elements to changing demands, either under normal or psychopathological conditions. Specifically, Project 1 focuses on the opioid peptide family pro- dynorphin, which is co-stored with AVP in hypothalamic magnocellular neurons. Since AVP is a known ACTH/B- Endorphin secretagogue, a potential role of dynorphin in this stress-related function will be explored. In addition the posterior lobe and the anterior lobe dynorphin systems will serve as valuable models for studying its biosynthesis and regulation. Project 2 is a preclinical proposal looking at the effect of variables such as age, sex and tricyclic treatment on the cellular regulation of POMC in the anterior lobe. Project 3 is a clinical project exploring the HPA axis in major depression with basal measures and challenge studies using corticosteroids and CRF. Project 4 is a collaborative inter-university effort focused on CRF challenges in depression. The multidisciplinary approach involves the use of molecular biology immunohistochemistry, peptide measurements and characterization, biosynthesis and release studies and behavioral and pharmacological challenges. Information derived from each of the projects will be considered in the interpretation of results from the other projects. The net result should be increased insight in the biology of stress and depression.